. The long term objective of this research is to provide a rational, mechanistic basis for improving the oral therapy of nucleoside drug analogues effective against HIV.The specific aims of the proposed research are: (1) To investigate the intestinal absorption mechanism of anti-HIV nucleoside analogues and to investigate the molecular basis for potential drug-drug and drug-nutrient absorption interaction; (2) To investigate the intestinal luminal, brush border and cytosolic metabolism and chemical stability of nucleoside analogues; (3) To construct a database that can be used for investigating the molecular-structural requirements of nucleoside analog oral absorption;and (4) To develop predictive models that will be used to correlate in vitro/in situ results with extent of absorption data in humans and to develop models that will predict bioavailability variability in humans. The investigator believes that the results of the proposed research will further the understanding of the factors that affect the oral efficacy of nucleoside drug analogues allowing for efficient and rational drug design and that the mechanistic insight gained will allow for improved and consistent nucleoside drug therapy leading to a decrease in therapy limiting side effects, to less variable systemic availability and blood levels and, ultimately, to improved oral anti-HIV drug therapy.